Our previous work showed that down-regulation of a critical IAP molecule using RNA interference techniques is capable of overcoming an important barrier to cancer cell death in intrinsically apoptosis-resistant human lung cancer cells. We have now performed preclinical work investigating several members of a novel drug class which inhibits the same IAP molecule pharmacologically and determined its efficacy in lung cancer cells. Our results appeared to show that all members tested from this new pharmacologic drug class are as effective as RNA interference techniques. However, in two lung cancer cell lines, cell death was not achieved. In contrast, in the majority of lung cancer cells, these small molecule drugs can exert similar effects of reversing cell-death (apoptosis) resistance, rendering these cancer cells neo-susceptibility to apoptosis induction and resulting in cancer cell death. Our continuing work is focused on completing the necessary preclinical work to translate this drug class into the clinical setting and delineating the mechanism(s) for drug resistance of this small molecule mimic in lung cancer, as this would hold direct implications as to the appropriate patients who should and should not receive this drug in a clinical trial. In this first goal, we are taking three approaches: 1) to bring this new drug class directly into clinical trials upon completion of preclinical studies, provided the availability of the drug for use in the NIH Clinical Center;2) to investigate the effectiveness of creating a targeted nanoparticle delivery of our (already effective in-vitro) RNAi modulation of the apoptosis pathway;and 3) to develop a targeted delivery approach of pro-apoptosis payload using a virus-like particle (VLP) construct. In approach #1, we are progressing to in-vivo evaluation in small animal models using the novel combination of this small molecule mimic and an upstream apoptosis inducer. In approach #2, we have performed in-vitro testing a nanodelivery platform for anti-cancer therapy to determine the critical modifications necessary to produce a viable clinically useful nanodelivery vehicle. Preliminary results are promising. In approach #3, our preliminary work suggests the need for inrease TRAIL receptor stimulation by the TRAIL-targeted VLP and we have worked with our collaborators to re-design the targeting ligand to better effect stimulation of the apoptosis pathway upon VLP docking with the lung cancer cell. A second generation VLP construct is currently being jointly evaluated.